CN1024011C - 头孢菌素化合物的生产方法 - Google Patents
头孢菌素化合物的生产方法 Download PDFInfo
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- CN1024011C CN1024011C CN87101581A CN87101581A CN1024011C CN 1024011 C CN1024011 C CN 1024011C CN 87101581 A CN87101581 A CN 87101581A CN 87101581 A CN87101581 A CN 87101581A CN 1024011 C CN1024011 C CN 1024011C
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 229930186147 Cephalosporin Natural products 0.000 title claims description 9
- 229940124587 cephalosporin Drugs 0.000 title claims description 9
- -1 cephalosporin compounds Chemical class 0.000 title description 237
- 150000001875 compounds Chemical class 0.000 claims abstract description 116
- 238000000034 method Methods 0.000 claims abstract description 47
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 38
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims description 33
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
- 150000002148 esters Chemical group 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- 230000000903 blocking effect Effects 0.000 claims description 9
- 125000003368 amide group Chemical group 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 150000001780 cephalosporins Chemical class 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 5
- 150000001782 cephems Chemical group 0.000 claims description 3
- 108090000765 processed proteins & peptides Chemical class 0.000 claims description 3
- XTTGYFREQJCEML-UHFFFAOYSA-N tributyl phosphite Chemical compound CCCCOP(OCCCC)OCCCC XTTGYFREQJCEML-UHFFFAOYSA-N 0.000 claims description 3
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 claims description 3
- 150000003952 β-lactams Chemical class 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 165
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 115
- 239000000243 solution Substances 0.000 description 76
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 57
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 55
- 230000002829 reductive effect Effects 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 125000000217 alkyl group Chemical group 0.000 description 35
- 239000002585 base Substances 0.000 description 35
- 239000012046 mixed solvent Substances 0.000 description 32
- 238000001035 drying Methods 0.000 description 31
- 238000002329 infrared spectrum Methods 0.000 description 31
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 26
- 238000001556 precipitation Methods 0.000 description 25
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 125000000623 heterocyclic group Chemical group 0.000 description 21
- 239000010410 layer Substances 0.000 description 21
- 229910052760 oxygen Inorganic materials 0.000 description 19
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 19
- 229910052799 carbon Inorganic materials 0.000 description 18
- 239000001301 oxygen Substances 0.000 description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 17
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 15
- 238000005406 washing Methods 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 13
- 150000001721 carbon Chemical group 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
- 238000002156 mixing Methods 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 11
- 125000003710 aryl alkyl group Chemical group 0.000 description 11
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000000843 powder Substances 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000005755 formation reaction Methods 0.000 description 10
- HQOQSFITXGQQDM-SSDOTTSWSA-N methyl (6R)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical class COC(=O)C1=CCS[C@@H]2CC(=O)N12 HQOQSFITXGQQDM-SSDOTTSWSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 125000004423 acyloxy group Chemical group 0.000 description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 description 9
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- JWGFQCLMHAYABI-ZCFIWIBFSA-N (6r)-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(CO)=C(C(O)=O)N2C(=O)C[C@H]21 JWGFQCLMHAYABI-ZCFIWIBFSA-N 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 6
- 238000005886 esterification reaction Methods 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 125000001453 quaternary ammonium group Chemical group 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 125000001118 alkylidene group Chemical group 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 125000004450 alkenylene group Chemical group 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 description 4
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 4
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- URYAFVKLYSEINW-UHFFFAOYSA-N Chlorfenethol Chemical compound C=1C=C(Cl)C=CC=1C(O)(C)C1=CC=C(Cl)C=C1 URYAFVKLYSEINW-UHFFFAOYSA-N 0.000 description 3
- 125000000030 D-alanine group Chemical group [H]N([H])[C@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
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- 235000019253 formic acid Nutrition 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 150000002903 organophosphorus compounds Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- ZMLJHXQHPNGPJP-UHFFFAOYSA-N 4-aminoimidazol-2-one Chemical compound NC1=NC(=O)N=C1 ZMLJHXQHPNGPJP-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
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- 239000007810 chemical reaction solvent Substances 0.000 description 1
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- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002711 cysteinyl group Chemical group 0.000 description 1
- 125000002697 cystyl group Chemical group 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
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- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
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- RVDJLKVICMLVJQ-UHFFFAOYSA-N diethoxy(phenyl)phosphane Chemical compound CCOP(OCC)C1=CC=CC=C1 RVDJLKVICMLVJQ-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 150000002170 ethers Chemical class 0.000 description 1
- HOCOIDRZLNGZMV-UHFFFAOYSA-N ethoxy(oxido)phosphanium Chemical compound CCO[PH2]=O HOCOIDRZLNGZMV-UHFFFAOYSA-N 0.000 description 1
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- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
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- 230000003301 hydrolyzing effect Effects 0.000 description 1
- NIAGBSSWEZDNMT-UHFFFAOYSA-N hydroxidotrioxidosulfur(.) Chemical compound [O]S(O)(=O)=O NIAGBSSWEZDNMT-UHFFFAOYSA-N 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- JMANUKZDKDKBJP-UHFFFAOYSA-N imidazo[1,5-a]pyridine Chemical compound C1=CC=CC2=CN=CN21 JMANUKZDKDKBJP-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000005233 imidazopyridazines Chemical class 0.000 description 1
- 125000004129 indan-1-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])([H])C2([H])* 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
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- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
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- 125000001288 lysyl group Chemical group 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
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- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- 125000002073 methionyl group Chemical group 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
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- 229940017219 methyl propionate Drugs 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical compound CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
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- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000000405 phenylalanyl group Chemical group 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 150000003018 phosphorus compounds Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical group [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 1
- 150000004892 pyridazines Chemical class 0.000 description 1
- AEMXNRIHRLEYAK-UHFFFAOYSA-N pyridin-2-yl acetate Chemical compound CC(=O)OC1=CC=CC=N1 AEMXNRIHRLEYAK-UHFFFAOYSA-N 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- KZVLNAGYSAKYMG-UHFFFAOYSA-N pyridine-2-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=N1 KZVLNAGYSAKYMG-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 125000002072 seryl group Chemical group 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- 150000003566 thiocarboxylic acids Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
- 229940103494 thiosalicylic acid Drugs 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 125000001239 threonyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical compound CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 description 1
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000001982 tryptophyl group Chemical group 0.000 description 1
- 125000002233 tyrosyl group Chemical group 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 125000002114 valyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
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Abstract
具有下列通式的化合物或其盐的生产方法,
Description
本发明涉及通式[Ⅰ]化合物方便的工业生产方法,
其中,R代表氢原子,酰基或与酰基不同的保护基团,Q代表氢原子或酯基,Y代表亲核化合物的残基,虚线表示2位或3位双键(化合物[Ⅰ]应认为包括其盐,下文内同样适用),生产该类化合物所用的起始原料是具有通式[Ⅱ]化合物。
其中,R,Q及虚线所代表的与上述内容相同(化合物[Ⅱ]应认为包括其盐,下文内同样适用);和亲核化合物及它们的盐。
化合物[Ⅰ]是一种重要的抗菌化合物,或者用作为合成抗菌化合物的中间体,制备化合物[Ⅰ]的方法已被广泛研究。工业上应用的开始原料头孢烯化合物,主要是通过发酵生产的头孢菌素C(CPC),或从其衍生出来的3-乙酰氧甲基头孢烯化合物以及脱乙酰基头孢菌素C(DCPC)或者DCPC或CPC在化学反应或酶反应条件下产生的
3-羟甲基头孢烯化合物[Ⅱ]。以及化合物[Ⅰ]已用亲核化合物替代它们的乙酰氧基或羟基生产。然而,为了将亲核基团替代3-乙酰氧甲基头孢烯化合物的乙酰氧基,由于后者的反应性能相对低些,反应时需要加热,或用大量酸性催化剂,在如此条件下头孢菌素分解而使产量下降是不可避免的;并且要使用大量强酸,在工厂设备上受到一定限制,或者需要进行麻烦的后处理。另一方面,包括以更活泼基团替代3-羟甲基头孢烯化合物[Ⅱ],再使反应生成物与亲核化合物反应的方法已被研究。列举这些方法于后:
方法(1):包括以卤素基团替代3位羟基,再使反应生成物与亲核化合物反应(比利时专利719,710);
方法(2):包括以更活泼的基团酰氧基(例如乙酰乙酰氧基)替代3位羟基(与乙酰氧基比较),再使反应生成物与亲核化合物反应(英国专利1,544,103)以及
方法(3):包括使化合物[Ⅱ]与亲核化合物以及环状磷化物,在有机溶液中反应(英国专利2,108,114和2,147,900)。环状磷化物的部分结构式为:
[其中W,W1代表O,S,NH或烃基取代的氨基]。
然而,方法(1)和方法(2)的二个反应过程要求单独进行,使反应步骤增加,并且要花大量劳动力而降低了产率。还有在方法(1)中,当羟基卤代很容易发生时,容易发生与4位羟基和3位羟基形成内酯的副反应。为防止起见,需将4位羟基酯化。该酯化反应自然随后要脱酯化反应。这使方法更复杂化了。在方法(2)中,要指望得到较好的反应性,取决于3-酰氧基甲基的酰氧基的种类,但这不是足够的,还取决于所用的酰化剂;容易发生形成内酯环的副反应的话,便使产量降低。在方法(3)中,所用含有环内双键的环状磷化物,对空气中的湿气是不稳定的,容易水解。再有,环状磷化物相对说来是昂贵的,因而对工业上大量生产不利。
迄今尚未发现以化合物[Ⅱ]和亲核化合物,生产最终产物[Ⅰ]作为商品)的完全满意的方法。从大量需要最终产品[Ⅰ]的观点出发,要求有一个便利的方法。
情况如前述,本发明者已经对头孢菌素化合物[Ⅰ]不同制备法,展开了广泛的研究,结果发现高质量化合物意外地通过单纯的步骤,以高产量制得。反应步骤包括:将化合物[Ⅱ](由发酵培养产生的高效物质DCPC或CPC通过化学反应或酶反应制得)与亲核化合物和化合物[Ⅲ]进行反应。
[其中R1,R2和R3各代表具有不超过8个碳原子的烃基,R1和R2,R1和R3或者R2和R3可以结合起来成为多亚甲基],在从化合物[Ⅱ]生产化合物[Ⅰ]的领域里从未用过化合物[Ⅲ];同时还发现化合物[Ⅲ]价格并不昂贵,所以最终产物[Ⅰ]能以工业规模进行大量制备。进一步发现,从工业应用观点出发,使用化合物[Ⅲ]具有以下有利的特色:
1.化合物[Ⅲ]与上述已知方法(3)中所用的环状磷化物相比,是比较稳定的,该法便于使用和处理化合物[Ⅲ]。
2.磷化物[Ⅲ]的酯键能被水解,随着反应进行所生成的相应的副产物醇,可以容易地采取蒸馏方法,从所需化合物中除去。
3.化合物[Ⅲ]可作为一种还原剂,因而有能力防止产物[Ⅰ]因氧化作用而产生颜色。
4.用化合物[Ⅲ]进行反应是温和的,且不放热,能有效地使反应在室温下进行,毋需加热和冷却,基于该发现,目前的发明得以完成。
因此,目前的发明涉及制备化合物[Ⅰ]的方法,特征为:由化合物[Ⅱ]与亲核化合物及化合物[Ⅲ]起反应。
在上述通式中,R代表氢原子,酰基或不同于酰基的保护基团,酰基在β-内酰胺类抗生素领域里是众所周知的,已知的一些举例为如酰基取代青霉素衍生物6位氨基,或酰基取代头孢菌素衍生物7位氨基。这些酰基的特殊例子包括从羧酸消除OH基后的酰基,进一步以下列通式举例:Ra-
CO-[Ⅳ],[其中Ra代表氢原子,烷基*,苯基*或杂环基团];
,[其中Rb代表氢原子,氨基酸残基,氨基的保护基团,或Rd-(CH2)n1-CO-,{其中Rd代表杂环基团*,n1表示0~2的整数},Rc代表烷基,苯基*和杂环基团*];Re-Rf-CO-[Ⅵ],[其中Re代表以通式RG-C=N~O-Rh表示的基团,{其中Rg代表烷基*,杂环基团*或苯基*,Rh代表氢原子,烷基*,或以通式-Ri-Rj表示的基团(其中Ri代表亚烷基或亚烯烃基,Rj代表苯基*,羧基或酯,或其单烷胺基或二烷胺基酯},Rf代表键本身,或以通式
表示的基团,(其中Rk代表烷基,苯基*或噻唑基*)];化合物[Ⅶ],
[其中R1代表羟基,羟基磺酰氧基,羧基,脲基*,氨磺酰基,磺基或苯氧基*,羰基甲酰氧基;Rm代表氢原子,烷基,烷氧基,卤原子,硝基,羟基];Rn-Ro-CH2-CO-[Ⅷ],[其中Rn代表氰基,苯基*,苯氧基*,酰氧基,烯烃基*或杂环基团;Ro代表键本身或-S-],等等。至于前面提到的符号Ra~Ro所代表的基团以及通篇说明书详述的基团,下列将用碳原子数目分别定义,当特别指定时,作相应修改,除非另作解释。当它们是“可任意选择的取代基”,在其右上角附有*号。例如,“可任意选择的烷基”,则以“烷基*”表示。在这一情况中,取代基的数目不只限于一个而是两个到几个取代基(取决于被取代的基团),可取的为2~8个取代基,更佳为2~3个取代基,其可以是同一个或互相各异。更可取的烷基取代基为直链或支链的具1~6个碳原子的低级烷基,例如,甲基,乙基,正丙基,异丙基,正丁基,异丁基,叔丁基,正戊基,异戊基,正己基,异己基等。特别是“低级烷基”意味着具有1~6个碳原子的烷基,除非另有指定。更可取的烯烃基团为具有2~6个碳原子的直链或支链的低级烯烃基团,例如乙烯基,烯丙基,异丙烯基,2-甲基烯丙基,2-丁烯基,3-丁烯基等。作为5-8员杂环基团述及的为含一个到几个(更可取的为1~4个)杂原子,杂原子选自氮原子(其任意选择的氧化物),氧原子和硫原子之间,或者其稠环,那些在碳原子本身带键的基团,有如下实例:2-或3-吡咯基,2-或3-呋喃基,2-或3-噻吩基,2-或3-吡咯烷基,2-,3-或4-吡啶基,N-氧撑-2-,3-或4-吡啶基,2-,3-或4-哌啶基,2-,3-或4-吡喃基,2-,3-或4-噻喃基,吡嗪基,2-,4-或5-噻唑基,2-,4-或5-噁唑基,3-,4-或5-异噻唑基,3-,4-或5-异噁唑基,2-,4-或5-咪唑基,3-,4-或5-吡唑基,3-或4-哒嗪基,N-氧撑-3-或-4哒嗪基,2-,4-或5-嘧啶基,N-氧撑-2-,4-或5-嘧啶基,哌嗪基,4-或5-(1,2,3-噻二唑)基,3-或5-(1,3,4-噻二唑)基,1,3,4-噻二唑基,1,2,5-噻二唑基,4-或5-(1,2,3,-噁二唑)基,3-或5-(1,2,4-噁二唑)基,1,3,4-噁二唑基,1,2,5-噁二唑基,1,2,3-或1,2,4-三唑,1H或2H-四唑基,吡啶并[2,3-d]嘧啶基,苯并吡喃基,1,8-,1,4-,1,6-,1,7-,2,7-或2,6-亚萘基,喹啉基,噻吩并[2,3-d]吡啶基,咪唑并[1,2-a]吡啶鎓-1-基,2,3-环戊烯-1-吡啶鎓(Pyridinio),咪唑并[1,5-a]吡啶鎓-2,咪唑并[1,2-b]哒嗪鎓-1,等等,上述基团可供通常应用。更可取的烷氧基是具有1~6个碳原子的直链或支链低级烷氧基团,例如:甲氧基,乙氧基,正丙氧基,异丙氧基,正丁氧基,异丁氧基,仲丁氧基,叔丁氧基,正戊氧基,异戊氧基,正己氧基,异己氧基等。卤素用氟,氯,溴,碘。氨基酸残基为甘氨酰基,丙氨酰基,缬氨酰基,亮氨酰基,异亮氨酰基,丝氨酰基,苏氨酰基,半胱氨酰基,胱氨酰基,甲硫氨酰基,a或β-天冬胺酰基,a-或r-谷氨酰基,赖氨酰基,精氨酰基,苯丙氨酰基,苯甘氨酰基,酪氨酰基,组氨酰基,色氨酰基,脯氨酰基等。氨基酸残基不仅包括D-氨基酸残基,而且包括L-氨基酸残基。更可取的亚烷基为具有1~3个碳原子的低级亚烷基,例如:亚甲基,亚乙基,亚丙基,异亚丙基等。可取的亚烯基为具有2~4个碳原子的低级亚烯基,例如:亚乙烯基,亚丙烯基等。所用羧酸酯为具有1~6个碳
原子的低级烷基酯,例如:甲酯,乙酯,丙酯,正丁酯,异丁酯,叔丁酯等。
在β-内酰胺类和肽类合成领域内所用的一些氨基保护基团,能方便地应用于本工作的目的,以Rb表示。具体例子为:芳香酰基,如邻苯二甲酰基,甲苯酰基,萘甲酰基,苯甲酰基,氯代苯甲酰基,对硝基苯甲酰基,对叔丁基苯甲酰基,对叔丁基苯磺酰基,苯磺酰基,甲苯磺酰基,苯乙酰基;脂肪酰基,如甲酰基,乙酰基,丙酰基,戊酰基,己酰基,正癸酰基,丙烯酰基,新戊酰基,一氯乙酰基,二氯乙酰基,三氯乙酰基,甲磺酰基,乙磺酰基,樟脑磺酰基,三氟乙酰基,马来酰基,琥珀酰基等;经酯化的羧基,如甲氧羰基,乙氧羰基,叔丁氧羰基,异丙氧羰基,2-氰乙氧羰基,β,β,β-三氯乙氧羰基,β-三甲硅乙氧羰基,β-甲磺酰乙氧羰基,苄氧羰基,对硝基苄氧羰基,对甲氧基苄氧羰基,二苯甲基氧羰基,甲氧基甲基氧羰基,乙酰基甲基氧羰基,异冰片基羰基,苯氧基羰基等;取代氨基甲酰基,如甲基氨基甲酰基,苯基氨基甲酰基,萘基氨基甲酰基等;此外还有三苯甲基,1-甲基-2-乙氧羰基乙烯基,2,2-二乙氧羰基乙烯基,3-氧代丁烯-(1)-基-1,2-硝基苯硫基,亚苄基,4-硝基亚苄基,三烃硅烷基,苄基,对硝基苄基;磷酰基,如二乙基磷酰基,二甲基磷酰基,二苯磷酰基,二异丙基磷酰基,二异丁基磷酰基,二丁基磷酰基,邻羟苯基磷酰基,甲基(邻羟苯基)磷酰基等;氧膦基,如二甲基氧膦基,二苯基氧膦基等;膦酰基,如苯基膦酰基,丁基膦酰基等,它们是不同于酰基的氨基保护基团。为本发明的目的,上面提到的保护基团可供任意选用。
在这些可供任意选择的取代基团中,烷基,烯烃基和亚烯基可以具有1~3个取代基,如环烷基*,环烯烃基*,芳基*,杂环基团*,烷氧羰基,酰基,氧基,卤素,氰基,三氟甲基,羟基,烷氧基,芳烃*氧基,酰氧基,氨基甲酰氧基,羟磺酰氧基,烃磺酰氧基,芳烃*磺酰氧基,硝基,氨基,羧基,氨基羰基,烃硫代羰基,巯基,烃硫基,氨基烃硫基,酰基氨基烃硫基,芳烷基*硫基,芳烃*硫基,杂环*硫基,季铵*,烯烃基等。
用作为取代烷基的,以通式[Ⅸ]表示:
[其中n2表示0~3的整数,Rp和Rq各自代表氢原子,烷基,环烷基*,芳烷基*,芳基*,杂环基团*,烷氧羰基,酰基,或Rp和Rq合在一起表示氧基;Rr代表氢原子,烷基,环烷基*,环烯烃基*,芳基,杂环基团*,卤素,氰基,羟基,烷氧基,芳氧基*,酰氧基,氨基甲酰氧基,烃磺酰氧基,羟磺酰氧基,芳烃磺酰氧基*,硝基,氨基,羧基,烷氧羰基,氨基羰基,烷硫代羰基,酰基,巯基,烷硫基,氨基烷硫基,酰基氨基烷硫基,硫代*芳烷基,硫代*芳烃硫代杂环*或季铵*]。作为环烷基团,更可取的是那些具有3-8个碳原子的,所用的环烷基团由下列基团构成,例如:环丙基,环丁基,环戊基,环己基,环庚基,金刚烷基等。用作为芳基的,尤其是苯基,α-萘基,β-萘基,联苯基和蒽基,特别是苯基和萘基等是常用的。用作为芳烷基的是苄基,菲基,苯丙基或萘甲基。用作为酰基的,由下列基团构成,例如:甲酰基,烷羰基,芳基*羰基,芳烷*羰基,杂环*乙酰基,特别是乙酰基,丙酰基,正丁酰基,异丁酰基,正戊酰基,正己酰基,苯甲酰基,4-羟苯甲酰基,4-甲氧基苯甲酰基,苯乙酰基,4-羟苯乙酰基,4-甲氧基苯乙酰基,2-噻吩羰基,2-呋喃羰基,2-,4-或5-噻唑乙酰基,2-或3-噻吩乙酰基,2-或3-呋喃乙酰基,2-氨基-4或5-噻唑乙酰基等。用作为季铵基团的,由下列基团构成,例如:吡啶鎓,喹啉鎓等。这些季铵基团可以和羧酸基的相反离子(-COO-)形成分子内盐。用作为环烯烃基团的,由以下基团构成,例如:1-环丙烯基,1-环己烯基,1-环庚烯基等,具有3-8个碳原子。
用作为环烷基*,环烯羟基*,芳烷基*,芳基*,杂环基团*和季铵*等取代基的,由以下基团构成,例如:烷基,烷氧基,烯烃基,芳基,芳烷基,巯基,烃硫基,芳烃硫基,芳烷硫基,烃磺酰基,芳烃磺酰基,芳烷磺酰基,羟基,氧基,硫代氧基,卤素,硝基,氨基,氰基,氨基甲酰基,羧基,酰基,酰氧基,酰氨基,羟烷基,羧烷基,卤代烷基,一或二烷基氨基烷基等。
用作为苯氧基*的取代基,正如前面所描述
的,制备芳基的那些基团。此外,用作为噻唑基*取代基的,由具有3-4个碳原子的酰氨基构成,后者用下列基团取代,例如:烷基,烷氧基,卤素,羟基,氨基等。用作为杂环基团*取代基的,可以由苯基构成,后者用烷基,烷氧基,卤素,硝基,氨基等取代。用作为脲基*取代基的,由以下基团构成,例如:磺基,氨基甲酰基,氨磺酰基,脒基,具有1-3个碳原子的烷基,以合适的钠盐或钾盐形式存在。用作为氨磺酰基*取代基的,由具有1-3个碳原子的低级烷烃,脒基等构成。用作为亚烯基*取代基的,由羧基,氰基等构成。
通式代表两种异构体或其混合物。
在上述以R表示的酰基中,以通式Ra-CO-表示酰基的具体例子,尤其是甲酰基,乙酰基己酰基,苯甲酰基,对硝基苯甲酰基,3-(2,6-二氯苯基)-5-甲基异噁唑基4-羰基,5-甲基-3苯基-4-异噁唑羰基和4-乙基-2,3-二氧基-1-噁嗪羰基。
作为酰基的实际例子,以通式
表示,基团有:D-丙氨酰基,苄基-N-苄酯基-r-D-谷氨酰基-D-丙氨酰基,D-苯基甘氨酰-D-丙氨酰基,N-苄酯基-D-丙氨酰基,N-苄酯基-D-苯基甘氨酰基,D-丙氨酰基-D-苯基甘氨酰基,r-D-谷氨酰基-D-丙氨酰基,2-(4-乙基-2,3-二氧-1-哌嗪基羧酰氨基)-2-苯乙酰基,2-(4-乙基-2,3-二氧基-1-哌嗪基羧酰氨基)-2-(4-磺氧苯基)乙酰基,N-(4-乙基-2,3-二氧基-1-嗪基羰基)-D-丙氨酰基,N-(4-乙基-2,3-二硫-1-哌嗪羰基)-D-苯基甘氨酰基,2,2-双-(4-乙基-2,3-二氧-1-哌嗪基羧酰氨基)乙酰基,2-(2-氨基-4-噻唑基)-2-(4-乙基-2,3-二氧-1-哌嗪基羧酰氨基)乙酰基,2-(4-羟基-6-甲基烟酰氨基)-2-苯基-乙酰基,2-(4-羟基-6-甲基烟酰氨基)-2-(4-羟基苯基)乙酰基,2-{5,8-二氢-2-(4-甲酰基-1-哌嗪基)-5-氧代吡啶并[2,3-d]嘧啶-6-羧酰氨基}-2-苯乙酰基,2-(3,5-二氧-1,2,4-三嗪-6-羧酰氨基)-2-(4-羧基苯基)乙酰基,2-(3-亚糠基氨基-2-氧代咪唑烷-1-羧酰氨基)-2-苯乙酰基,2-(香豆素-3-羧酰氨基)-2-苯乙酰基,2-(4-羟基-7-甲基-1,8-[1,5-二氮杂萘]-3-羧酰氨基)-2-苯乙酰基,2-(4-羟基-7-三氟甲基喹啉-3-羧酰氨基)-2-苯乙酰基,N-[2-(2-氨基-4-噻唑基)乙酰基]-D-苯基甘氨酰基,2-(6-溴-1-乙基-1,4-二氢-4-氧代噻吩并[2,3-d]吡啶-3-羧酰氨基)-2-苯乙酰基,2-(4-乙基-2,3-二氧-1-哌嗪基羧酰氨基)-2-噻吩乙酰基,2-(4-正戊基-2,3-二氧-1-哌嗪基羧酰氨基)-2-噻吩乙酰基,2-(4-正辛基-2,3-二氧-1-哌嗪基羧酰氨基)-2-噻吩乙酰基,2-(4-环己基-2,3-二氧-1-哌嗪基羧酰氨基)-2-噻吩乙酰基,2-[4-(2-苯乙基)-2,3-二氧-1-哌嗪基羧酰氨基]-2-噻吩乙酰基,2-(3-甲磺酰基-2-氧代咪唑烷-1-羧酰氨基)-2-苯乙酰基,2-(3-亚糠基氨基-2-氧代咪唑烷-1-羧酰氨基)-2-(4-羟基苯)乙酰基,2-(4-乙基-2,3-二氧-1-嗪基羧酰氨基)-2-(4-苄氧苯基)乙酰基,2-(4-乙基-2,3-二氧-1-哌嗪基羧酰氨基)-2-(4-甲氧基苯基)乙酰基,2-(8-羟基-1,5-二氮杂萘-7-羧酰氨基)-2-苯乙酰基等。
作为酰基的具体例子,以通式Re-Rf-CO-表示,基团有:N-[2-(2-氨基-4-噻唑基)-2-甲氧基亚氨基乙酰基]-D-丙氨酰基,N-[2-(2-氨基-4-噻唑基)-2-甲氧基亚氨基乙酰基]-D-苯基甘氨酰基,2-(2-氨基-4-噻唑基)-2-[2-(2-氨基-4-噻唑基)-2-甲氧基亚氨基乙酰基]乙酰基,2-(2-氯乙酰氨基-4-噻唑基)-2-甲氧基亚氨基乙酰基,2-(2-氨基-4-噻唑基)-2-甲氧基亚氨基乙酰基,2-(2-氨基-4-噻唑基)-2-乙氧基亚氨基乙酰基,2-(2-氨基-4-噻唑基)-2-丙氧基亚氨基乙酰基,2-(2-氨基-4-噻唑基)-2-丁氧基亚氨基乙酰基,2-(2-氨基-4-噻唑基)-2-苄氧基亚氨基乙酰基,2-(2-氨基-4-噻唑基)-2-烯丙氧基亚氨基乙酰基,2-(2-氨基-5-
氯-4-噻唑基)-2-甲氧基亚氨基乙酰基,2-(2-氨基-5-溴-4-噻唑基)-2-甲氧基亚氨基乙酰基,2-(2-氨基-4-噻唑基)-2-羟亚氨基乙酰基,2-噻吩基-2-甲氧基亚氨基乙酰基,2-呋喃基-2-甲氧基亚氨基乙酰基,2-(1,2,4-噻二唑基-5)-2-甲氧基亚氨基乙酰基,2-(1,3,4-噻二唑)-2-甲氧基亚氨基乙酰基,2-(4-羟苯基)-2-甲氧基亚氨基乙酰基,2-苯基-2-甲氧基亚氨基乙酰基,2-苯基-2-羟亚氨基乙酰基,2-[4-(r-D-谷氨酰氧基)苯基]-2-羟亚氨基乙酰基,2-[4-(3-氨基-3-羧丙氧基)苯基]-2-羟亚氨基乙酰基等。
作为酰基的具体例子,以通式
表示,基团有:
表示,
α-磺基苯乙酰,α-羧基苯乙酰基,α-羟苯乙酰基,α-脲基苯乙酰基,α-硫代脲基苯乙酰基,α-氨磺酰基苯乙酰基,α-苯氧羰基苯乙酰基,α-(对甲苯氧基羰基)苯乙酰基,α-甲酰氧基苯乙酰基等。
作为酰基的具体例子,以通式Rn-Ro-CH2-CO-表示,基团有:氰乙酰基,乙酰乙酰基,苯乙酰基,苯氧乙酰基,5-氨基-5-羧基戊酰基,5-氧基-5-羧基戊酰基,4-羧基丁酰基,三氟甲基硫代乙酰基,氰甲基硫代乙酰基,1H-四唑基-1-乙酰基,噻吩乙酰基,2-(2-氨基-4-噻唑基)乙酰基,4-吡啶硫代乙酰基,2-噻吩硫代乙酰基,3,5-二氯-1,4-二氢-4-氧基吡啶-1-乙酰基,β-羧基乙烯基硫代乙酰基,2-(2-氨基甲基苯基)乙酰基等。
上述酰基中的氨基,羧基和/或羟基可以任意选择地加以保护。用来作为保护氨基的基团,与前面述及的Rb所表示的相似。用来作为保护羧基的基团,是在β-内酰胺化学和有机化学领域里常用的羧基保护基团。有以下例子:酯残基和甲硅烷基,更具体的有:甲基,乙基,正丙基,异丙基,叔丁基,叔戊基,苄基,对硝苄基,对甲氧基苄基,二苯甲基,1-茚满基,苯甲酰甲基,苯基,对硝苯基,甲氧基甲基,乙氧基甲基,苄氧基甲基,乙酰氧基甲基,新戊酰基甲基,β-甲基磺酰基,β-三甲基甲硅烷基乙基,甲基硫代甲基,三苯甲基,β,β,β-三氯乙基,β-碘乙基,三甲基甲硅烷基,二甲基甲硅烷基,乙酰甲基,对硝苯甲酰甲基,对甲磺酰苯甲酰甲基,酞酰亚胺基甲基,丙氧酰基甲基,1,1-二甲丙基,3-甲基-3-丁烯基,琥珀酰亚胺基甲基,3,5-二叔丁基-4-羟苄基,甲磺酰甲基,苯磺酰甲基,苯基硫代甲基,二甲胺乙基,吡啶1-氧化物-2-甲基,甲基亚硫酰基甲基,双(对-甲氧苯基)甲基,2-氰基,1,1-二甲基乙基等。用来作为保护羟基的基团,是在β-内酰胺抗生素、肽类化学和有机化学中常用的保护基团。它们是:酯残基,例如乙酰基,氯乙酰基等;经酯化的羧基,如β,β,β-三氯乙氧羰基,β-三甲基甲硅烷基乙氧羰基等;醚残基,如叔丁基,苄基,对硝苄基,三苯甲基,甲基硫代甲基,β-甲氧基乙氧甲基等;甲硅烷基残基,如三甲基甲硅烷基,叔丁基二甲基甲硅烷基等;乙缩醛残基,如2-四氢吡喃基,四甲氧基-4-四氢吡喃基等,上述保护基团可供任意选择,如同氨基和羧基保护基团的情况。
用作为以R表示的,且不同于酰基的保护基团,由不同于酰基的氨基保护基团构成,可应用前面述及的氨基保护基团。
通式[Ⅰ]及[Ⅱ]中的符号Q代表氢原子或酯残基。用作为以Q表示的酯残基,由下列基团构成,例如:C1~6烷基(如甲基,乙基,正丙基,异丙基,叔丁基,叔戊基等),芳烷基*(如苄基,对硝苄基,对甲氧基苄基,二苯甲基,双(对甲氧苯基)甲苯等)。
通式[Ⅰ]中的符号Y代表亲核化合物残基。作为亲核化合物,其特征为具有亲核性氮原子,碳原子或硫原子,到目前为止,凡涉及头孢菌素化学问题时,许多发表的论文报告已经对此作了广泛抽述。例如,这些报告包括上述英国专利1,544,103,2,108,144和2,147,900以及比利时专利719,710。这些已知的应用于头孢菌素化学领域里的亲核化合物,能广泛地应用于本发明。
可供应用的亲核化合物以含硫亲核化合物,含氮亲核化合物或含碳亲核化合物举例。作为含硫亲核化合物(Y-H),大量已知化合物能被应用,由下列化合物构成:例如,烷基*硫醇,烯基硫醇,芳基*硫醇,芳烷基*硫醇或具有1~5个氮原子的含氮杂环硫醇,杂环内也可用不同于氮原子的其他
杂原子,如氧原子和硫原子。含氮杂环硫醇包括其在母核上带有1~4个取代基的那些。用作为以Y表示的含氮杂环基团,由含氮六元杂环基团构成,如吡啶基,N-氧撑吡啶基,嘧啶基,哒嗪基,N-氧撑哒嗪基,三嗪基,喹唑啉基等及其稠环基团;由含氮五元杂环基团构成,如咪唑基,噻唑基,噻二唑基,噁二唑基,三唑基,四唑基等,及其稠环基团。用作为这些含氮杂环基团的取代基,由下列基团构成,例如,羟基,氨基,羧基,氧基,氨基甲酰基,低级烷基(如甲基,乙基,三氟甲基,丙基,异丙基,丁基,异丁基等);低级烷氧基,(如甲氧基,乙氧基,丙氧基,丁氧基等);卤素(如氯,溴等);或者具有带多价基团的不同取代基,如含C1-3的低级亚烷基,-S-基,-N<基等。当多价基团是C1-3的低级亚烷基时,取代基可以是低级的一或二烷氨基,吗啉基,羧基,磺基,氨基甲酰基,烷氧羰基,低级烷基氨基甲酰基,烷氧基,烷硫基,烷基磺酰基,酰氧基,吗啉基羰基等;当多价基团是-S-基及-N<基时,取代基可以是低级烷基以及具有上述取代基的低级亚烃基。当多价基团是-N<基,烷氧羰基,酰基,氨基甲酰基,低级烷基氨基甲酰基等可以直接联结。在这些含氮杂环基团上的取代基之间,较好的是羟基,氨基,低级烷基,低级的一或二烃胺基烃基,磺基烷基。具体应用的有下列化合物,例如:杂环硫醇,如吡啶硫醇(吡啶-2-硫醇),嘧啶硫醇(嘧啶-2-硫醇),甲基哒嗪硫醇,4,5-二氢-6-羟基-4-甲基-1,2,4-三嗪-3-硫醇,2-甲基-5,6-二氧基-1,2,5,6-四氢-1,2,4-三嗪-3-硫醇,咪唑硫醇(咪唑-2-硫醇,1,3,4-噻二唑-5-硫醇,1,2,3-噻二唑-5-硫醇,2-甲基-1,3,4-噻二唑-5-硫醇,噻唑硫醇,5-甲基-1,3,4-恶二唑-2-硫醇,1,2,3-三唑-5-硫醇,1-甲基四唑-5-硫醇,1-(2-二甲基胺乙基)四唑-5-硫醇,1-(2-磺基乙基)四唑-5-硫醇,1-磺基甲基四唑-5-硫醇,苯并咪唑硫醇,苯并噻唑硫醇,苯并亚唑硫醇等。除此而外,还有脂肪和芳香硫醇,如甲基硫醇,乙基硫醇,硫代酚等,硫脲,硫脲衍生物(N-甲基硫脲等),硫代酰胺衍生物(硫代乙酰胺,硫代苯甲酰胺等),硫氰酸盐(硫氰酸钾等),硫代羧酸(硫代水杨酸,二硫代羧酸等),硫代碳酸盐(乙基黄原酸钾,哌啶二硫代氨基甲酸钾等)。在这些含硫亲核化合物中,含氮杂环硫醇是优先应用的。含硫杂环化合物在反应时用其游离形式或其盐的形式,以盐形式时,用碱作用于酸基或用酸作用于碱基。作为含氮亲核化合物,许许多多已知的化合物能被应用。在它们中间有叠氮化物离子的金属盐类(如叠氮化钠),仲或叔级脂肪,芳香和芳脂胺类,以及含氮杂环化合物,如二烷胺(如二甲胺,二乙胺等),三烷胺(如三乙胺等),吡啶碱(吡啶和烷基吡啶等,具有2-5个杂原子的五元到七元杂环化合物,选自由硫,氧及氮原子组成的基团,杂原子中,至少有一个是氮原子,如嘧啶类,吗啉类,嘌呤类,哒嗪类,哌嗪类,吡唑类,咪唑类,三唑类和四唑类,稠杂环化合物(其中二个或更多,更可取的为2~3个这样的杂环为邻位稠合或邻位邻近稠合的,如咪唑并吡啶类,咪唑并哒嗪类及环烯烃基并吡啶类。
用作为更可取的含氮亲核化合物,以通式[Ⅹ]表示,
[其中n3表示0~5的整数,R8(当n3为2~5时,R8可以是相同的或互相不同的,或者与它们所附着的碳原子一起,形成5~7元饱和稠环或不饱和稠环)代表脂肪族基团,如低级烷基(甲基,乙基,正丙基,异丙基等);芳香基团,如苯基等;芳脂基团,如苯基(低级)烷基(苄基,苯乙基等);或者烷氧甲基,如甲氧基甲基,乙氧基甲基,正丙氧基甲基,异丙氧基甲基等;或者酰氧基甲基,如烷酰氧基甲基(乙酰氧基甲基等);氰基,甲酰基,氨基甲酰基,酰氧基(烷酰氧基(乙酰氧基),酯化的羧基,烷氧基(甲氧基,乙氧基,正丙氧基,异丙氧基等;芳氧基,如苯氧基等;芳烷氧基,如苄氧基等;烷硫基,如甲硫基,乙硫基等;芳硫基,芳烷硫基,羟基,N-~C1-6(低级)烷基氨基甲酰基(N-甲基氨基甲酰基,N-乙基氨基甲酰基等;N,N-二(低级)烷基氨基甲酰基,如N,N-二甲氨基甲酰基,N-N-二
乙氨基甲酰基等;N-(羟基(低级)烷基)氨基甲酰基,如N-(羟甲基)氨基甲酰基,N-(羟乙基)-氨基甲酰基等;羧基(低级)烷基,如羧甲基等,或者氨基甲酰基(低级)烷基,如氨基甲酰基甲基,氨基甲酰基乙基等。
在上述以Rs为代表的取代基中,更加可取的例子是C1-6烷基,C2-7烷氧甲基,氰基,甲酰基,氨基甲酰基,C1-6烷基及氨基甲酰基C1-6烷基。
进一步举例,作为更可取的含氮亲核化合物,可应用以通式[Ⅺ]为代表的那些,
[其中Rt和Ru各自代表氢原子或R8所规定的基团,或者Rt和Ru互相联结,和它们各自所附着的碳原子和氮原子一起,形成饱和的或不饱和的,具有1~5个杂原子(选自硫,氧和氮原子之间,1~4个杂原子为氮原子)的五元至七元杂环,例子为吡啶,哒嗪,嘧啶,吡嗪,噻唑,噁唑,咪唑,四唑,三唑,噻二唑,三嗪等,然后形成稠杂环]。特定的具体化合物有含氮杂环化合物,如吡啶,烟酸,烟酰胺,异烟酰胺,吡啶磺酸,吡啶基乙酸,吡嗪,2-氨基甲酰基吡嗪,嘧啶,咪唑,1-甲基咪唑,2,3-环戊烯基吡啶,烟酸甲酯,咪唑并[1,2-a]吡啶,咪唑并[1,5-a]吡啶,咪唑并[1,2-b]哌嗪,1-甲基吡咯烷,2-(4-吡啶基)乙磺酸,5-甲基四唑等。用作为含碳亲核化合物的,有下列化合物,例如:无机氰化物(如氰化钠),吡咯类及稠合吡咯类(如吲哚)等。
通式[Ⅰ]和[Ⅱ]中的虚线表明头孢烯环内的双键位于2位或3位。
在以通式[Ⅲ]表示的三价磷化合物中,R1,R2和R3分别代表烃基,其碳原子数不超过8,它们中间任何二个互相联结便形成多亚甲基。R1,R2和R3作为烃基,作为实例提到的有:烷基*,烯烃基*,环烷基*,酰基*,芳烷基*等,其碳原子数不超过8。R1作为可取的烃基,以实例表示:C1~8烷基,如上述C1~6烷基,庚基,辛基等;C5~8芳烷基,如苄基,苯乙基,呋喃基等;C2~8烯烃基,如烯丙基,2-丁烯基,3-丁烯基等;同时,这些C1~8烷基,C5~8芳烷基和C2~8烯烃基可带有1~3个取代基。这些取代基的实例已见前述,即有关Ra~RO的烷基,芳烷基和烯烃基的取代基。作为以R2和R3表示烷基时可取的实例为:除1-8烷基,C5-10C5-8芳烷基和C2-8烯烃基(就R1作过叙述)以外,下列C5-10芳基被应用:苯基,萘基,呋喃基等。这些C5-10芳基可以带1~3个取代基,其实例就Ra~RO已作过叙述。在通式[Ⅲ]的化合物中,R1,R2和R3当中的任何二个可以互相联结,形成多亚甲基;例如,二亚甲基,三亚甲基等;作为三价磷化物的特定实例提到的有:亚磷酸三酯,亚膦酸二酯,三价膦酸酯等。亚磷酸三酯的实例为亚磷酸三甲酯,亚磷酸三乙酯,亚磷酸三异丙酯,亚磷酸三正丁酯,亚磷酸异辛酯,亚磷酸三(2-乙基己基)酯,亚磷酸三(2-氯乙基)酯以及专著“Organic Phosphorus Compounds”Vol.5,pp·157~194(1973)所叙述的那些。亚膦酸酯的实例为:除苯基亚膦酸二甲酯,苯基亚膦酸二乙酯等以外,在专著“Organic Phosphorus Compounds”Vol.4,pp·361~391(1972)所叙述的那些。三价膦酸酯的实例为:除二乙基(三价)膦酸甲酯,二苯基(三价)膦酸乙酯等以外,在专著“Organic Phosphorus Com-pounds”Vol.4,pp·513~517(1972)所叙述的那些。这些磷化物[Ⅲ]可通过已知方法或类似的已知方法合成,它们可在本发明的方法中孤立地使用或作为反应混合物使用。在磷化物[Ⅲ]的某些化合物中,R1,R2和R3为独立的C18烷基是可取的,其中亚磷酸三甲酯,亚磷酸三乙酯,亚磷酸三异丙酯或亚磷酸三正丁酯更加可取,亚磷酸三酯,如亚
磷酸三甲酯或亚磷酸三乙酯,在工业上作用塑料和木材的火焰阻滞剂以及汽油和油漆的添加剂进行生产,故这些亚磷酸酯是容易获得的,应用于目前的发明特别有利。本发明的方法中,最终产物[Ⅰ]可以通过化合物[Ⅱ]与亲核化合物和三价磷化物[Ⅲ]反应来生产。
化合物[Ⅱ]不仅包括其酸基为羧基、磺基等的化合物(在R和Q基团中以游离酸形式存在),而且包括下列碱类及其形成的盐类,例如:无毒性的钠、钾阳离子;有机胺,如三乙胺,三正丁胺,二正丁胺,二环己胺,吡啶,可力丁,2,6-二甲基吡啶等。当R和Q含有碱性基团时,与有机酸成盐,如乙酸,酒石酸,甲磺酸等;与无机酸成盐,如盐酸,溴氢酸,硫酸,磷酸等。这样的盐以及分子内盐可形成自R或Y所含的季铵基以及来自羧酸基的相反离子。这些基团包含在起始化合物[Ⅱ]中。亲核化合物(取决于不同种类)与碱作用时能取其盐的形式,无毒性盐类是可取的;与酸作用时能取其盐的形式,无毒性盐类是可取的,两种盐类均包括在本发明所用的材料中。作为这种盐使用的那些化合物,在涉及化合物[Ⅱ]时已作描述。将化合物[Ⅱ],亲核化合物及化合物[Ⅲ]混合时的次序,不作特别限制,通常为:在有机溶剂中,磷化物[Ⅲ]或其溶于有机溶剂所成的溶液被加到化合物[Ⅱ]和亲核化合物的混合物中去,或者,在有机溶剂中,化合物[Ⅱ]或基溶于有机溶剂所成的溶液被加到亲核化合物和磷化物的混合物中去。
亲核化合物和磷化物[Ⅲ]与化合物[Ⅱ]的克分子比,可取的为一倍或更多倍,通常为1~10倍。亲核化合物或磷化物[Ⅲ]本身能用作反应溶剂,但在通常情况下,亲核化合物的用量为1~10倍,可取的为1~5倍(与化合物[Ⅱ]相比)。磷化物的用量为1~5倍,可取的为1~3倍,(与化合物[Ⅱ]相比)。
反应中所用有机溶剂应是对反应产生惰性的那些溶剂,例如:酰胺,如甲酰胺,二甲基甲酰胺,二甲基乙酰胺等;卤代烃,如氯乙烷,异丁基氯,二氯甲烷,氯仿,1,2,-二氯乙烷,四氯化碳,1,1,1-三氯乙烷,1,1,2-三氯乙烷,1,1,2,2-四氯乙烷,氟苯,二氯苯等;醚类,如二甲醚,二乙醚,四氢呋喃,二氧六环等;酯类,如乙酸甲酯,乙酸乙酯,乙酸异丁酯,丙酸甲酯,乙二醇碳酸酯等;腈类,如乙腈,丙腈,苄腈等;硝基化合物,如硝基甲烷,硝基乙烷等;酮类,如丙酮,甲乙酮等;烃类,如苯,甲苯,莱等;醇类,如甲醇,乙醇,丙醇,丁醇等;酸类,如乙酸,丙酸等。这些溶剂可用其合适的混合溶剂。尤其是用二氯甲烷,乙腈,甲酰胺,甲酰胺/乙腈,二氯甲烷/乙腈,二氯甲烷/四氢呋喃等混合溶剂,能得到中意的结果。
当有酸成分存在于反应混合物中,则反应迅速进行,在化合物[Ⅱ]中,当Q为氢原子时,即-COOQ为羧基,反应通常在短时间里完成,这是由于酸性的缘故。然而,当Q为酯残基时,当与钠、钾阳离子或有机胺形成盐的形式时以及当羧基因碱基的存在(如化合物[Ⅱ]或亲核化合物结构中所含的氨基等)而被中和时,反应便需要相对长的时间方能完成。在这种情况下,通过加酸来促进反应,以便缩短反应时间。为此目的,可采用一些不会使反应产生不良效果的酸,例如,羧酸,甲酸,乙酸,丙酸,丁酸,戊酸,苯甲酸等;磺酸,如甲磺酸,苯磺酸,对甲苯磺酸等;卤代氢,如氯代氢,溴化氢等,路易氏酸,如三氟化硼,氯化锌,三氯化铝等。它们中间象乙酸那样的羧酸特别可取。合适的反应温度和时间的选择,取决于化合物[Ⅱ],亲核化合物,磷化物[Ⅲ]和溶剂的种类。然而,反应时间通常是一分钟到大约10小时。反应进行时的温度范围宽广,-20°~80℃。反应时间通常可通过升高温度来缩短,但反应通常在室温或稍低的温度下进行(0~30℃),为达到避免头孢菌素因加热而分解的目的。反应通常在温和的条件下完成,在15~30℃进行反应几分钟到数小时。
在本发明的方法中,反应进行时,磷化物[Ⅲ]的酯键水解,生成相应的醇,通过减压恒沸蒸馏除去,醇随有机溶剂蒸出,使反应继续不断地进行,蒸出溶剂可回收重用。
所得头孢菌素化合物[Ⅰ]可从反应混合物中分离出来,有需要时,使所用的过量磷化物水解,随后使生成反应产物本身,用常规手段处理,如过滤,溶剂提取,改变pH值,相转移,盐析,结晶,重结晶,层析等。按以R表示的酰基种类,将化合物[Ⅰ]加到反应混合物中去,导致生成7-氨基头孢烯化合物(化合物[Ⅰ]中R以氢原子表示),后者是制备抗生素物质有用的中间体。化合
物[Ⅰ]不经分离,按已知方法或类似的已知方法,依次加莱二甲胺,三甲基甲硅烷基氯,五氯化磷,甲醇及水,从而使7位酰基裂解。当目标化合物[Ⅰ]为游离形式时,可按常规方法改变其成为本身的盐,被包括在化合物[Ⅰ]中。作为目标化合物[Ⅰ]的盐,无毒性的盐是可取的,这些盐象叙述起始化合物[Ⅱ]那样,举以下实例:酸基与碱金属形成的盐,如锂、钠、钾等;碱土金属,如钙、镁等;与胺类形成的盐,如二正丁胺,二环己基胺,二异丁胺,二叔丁胺,三丁胺,吡啶,2,6-二甲基吡啶,三丁胺等;碱基与无机酸形成的盐,如盐酸,硫酸等;与有机酸形成的盐,如草酸,乙酸,甲酸,三氯乙酸,三氟乙酸等;与磺酸形成的盐,如甲磺酸,甲苯磺酸,萘磺酸,樟脑磺酸等;与磷酸形成的盐,如甲基磷酸,二甲基磷酸,二苯基磷酸等;与膦酸形成的盐,如苯基膦酸等。
偶然发现,目前的发明中所用的起始化合物[Ⅱ]能通过发酵法制得[例如,Nature Vol.246,p·154(1973),Japanese Patent Applicafion Laid-Open №,491/1974等叙述的方法],或者将通过发酵法得到的产物作化学处理或酶催化处理[例如,Biochemical Journal Vol.81,pp·591~596(1961)叙述的方法]。还有亲核化合物能通过已知方法合成,下列文献书籍叙述这一方法或类似的方法:Robert C.Elderfield编:“Heterocyclic Compounds”;Weissberger等编:“The Chemistry of Heterocyclic Compounds”;J.Heterucyclic Chemistry Vol.15,p·1295(1978);Japanese Patent Application Laid-Open No.231684/1985。
抗菌化合物[Ⅰ](其中R为酰基)能用作为具有优良抗菌性质的抗菌素物质,其应用效果与文献报导方法一致[Japanese Patent Applications Laid-Open NO.72286/1974;48996/1977以及1280/1978等叙述的方法]。化合物[Ⅰ]也能用作合成具有优良抗菌效力的抗菌素物质的中间体,例如,化合物[Ⅰ]包含7-[2-(2-亚氨基-4-噻唑啉基-4)乙酰氨基]化合物[美国专利4,080,498等叙述],其合成步骤为,首先将化合物[Ⅰ](其中R为具有通式
的基团)按常规方法[Japanese Patent Application Publication Nos.41-13862/1966;40899/1970;Laid-Open No.34387/1972;美国专利3,632,578等]处理,使7位酰基裂解,然后使生成物与4-卤代-3-氧化丁酰基酰胺基化合物反应,随后使生成物与硫脲反应。所有得到的抗菌化合物显示出优良的抗菌性质,虽然在这些化合物中,性质上或多或少有些不同,这取决于3位上取代基的种类。
下列实例将进一步详细说明上述发明,但决不将其应用局限于本发明内。
实例中所用符号具有下列意义。
S:单峰,br:宽峰,d:双峰,dd:两组二重峰,t:三重峰,q:四重峰,ABq:AB型四重峰,m:多重峰,D2O:重水,%:重量百分比,TLC:薄层层析,DMSO-d6:六氘代二甲基亚砜,NaHCO3:碳酸氢钠。
核磁共振除特殊说明外均以化学位移(ppm)表示,以四甲基硅烷(DMSO-d6为溶剂)或2,2-二甲基-2-硅杂戊烷-5-磺酸钠(D2O为溶剂)作内标。“室温”指5-35℃。
实例1
将100ml四氢呋喃-二氯甲烷混合溶剂(1∶2,V/V),1.74g5-巯基-1-甲基-1H-四唑及2.3ml亚磷酸三甲酯依次加到5.03g7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)3-羟甲基-3-头孢烯-4-羧酸中,反应在18-22℃并搅拌下进行3.5小时。加30ml 1NHCl到反应液中去,该混合溶液搅拌30分钟,减压浓缩至约30ml,加进30ml二氯甲烷,用1N NaOH调节pH至5.6,分出有机层,水层中加入30ml四氢呋喃-二氯甲烷混合溶剂(1∶1,V/V),用2NHCl调节pH至2.0,分出有机层,水层用30ml上述混合溶剂(1∶1,V/V)提取,合并有机层,用饱和盐水溶液洗涤,用无水硫酸镁干燥。减压浓缩,浓缩液倒入300ml乙醚中,滤集沉淀,用醚洗涤,干燥,得5.86g(产率:97.4%)7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-(1-甲基-1H-四唑基-5)硫甲基-3-头孢烯-4-羧酸,本品为一白色粉末。
红外光谱(KBr):3350,2950,1773,1713,1530cm-1
核磁共振(DMSO-d6):δ1.20-2.40(6H,m,-(CH2)3-),3.60(2H,br,2-CH2),3.94(3H,S,-CH3),4.27(2H,br,
3-CH2),4.27(1H,t,J=8HZ,>CH-),5.00(1H,d,J=5HZ,C6-H),5.61(1H,dd,J=8×5HZ,C7-H),7.89(4H,S,C6H4<),8.76(1H,d,J=8HZ,-CONH-)ppm
实例2
将20ml二氯甲烷0.99g5-巯基-2-甲基-1,3,4噻二唑和1.7ml亚磷酸三乙酯依次加到2.52g7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸中,混合溶液于室温下搅拌3小时。将10ml1NHCl加入上述混合溶液中,此溶液在20~25℃搅拌30分钟,用1N NaOH调节pH至6.0,溶液分两层,水层中加入20ml四氢呋喃和20ml二氯甲烷的混合溶剂,用2NHCl调节pH至2.0,溶液分两层,水层用20ml四氢呋喃和20ml二氯甲烷的混合溶剂提取。合并有机层用无水硫酸镁干燥。减压浓缩后,加入150ml醚。滤集沉淀,醚洗,减压干燥,得2.87g(产率:92.9%)7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-(2-甲基-1,3,4-噻二唑基-5)硫甲基-3-头孢烯-4-羧酸,本品为白色粉末。
红外光谱(KBr):3330,2920,1775,1715,1530cm-1
核磁共振(DMSO-d6):δ1.30-2.40(6H,m,-(CH2)3-),2.71(3H,S,-CH3),3.62(2H,ABg,J=18HZ,2-CH2),4.37(2H,ABq,J=14HZ,3-CH2),4.76(1H,t,J=7HZ,>CH-),5.07(1H,d,J=5HZ,C6-H,5.65(1H,dd,J=8×5HZ,C7-H),7.92(4H,S,C6H4<),8.81(1H,d,J=8HZ,CONH)ppm
实例3
将4.0ml冰醋酸,151mg5-巯基-1-甲基-1H-四唑,0.50ml亚磷酸三乙酯依次加到580mg7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸二钾中。反应在25±2℃并搅拌下进行30分钟。将50ml乙醚加入反应液中,滤集沉淀,醚洗,减压干燥,得0.78g白争粉末。将粉末悬浮于8ml水中,用4NHCl调节pH至2.0,滤集沉淀,水洗,减压干燥,得550mg(产率:91.4%)7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-(1-甲基-1H-四唑基-5)硫甲基-3-头孢烯-4-羧酸,本品为一白色粉末。产物的红外和核磁共振光谱与实例1相符。
实例4
将232mg的5-巯基-1-甲基-1H-四唑溶于2.0ml甲酰胺和1.0ml乙腈混合溶剂中,依次向其中加入580mg7β-(D-5-羧基-5-邻苯二甲酰亚氨戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸二钾和0.50ml亚磷酸三乙酯。混合液在约1分钟内加热至30℃,在80±3℃并搅拌下反应9分钟。反应液用冰水浴冷却,向其中加入3ml1NHCl,搅拌30分钟,减压浓缩后,加入20ml水,10ml四氢呋喃,10ml二氯甲烷。混合液振摇后静置分层,分出有机层,水层用10ml四氢呋喃和10ml二氯甲烷的混合溶剂提取,合并有机层,用10ml水洗涤,无水硫酸镁干燥。减压浓缩,将50ml乙醚加入浓缩液中,滤集沉淀,减压干燥,得504mg(产率:83.8%)7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-(1-甲基-1H-四唑基-5)硫甲基-3-头孢烯-4-羧酸,本品为一白色粉末。产品的红外和核磁共振光谱与实例1相符。
实例5
将0.522g的5-巯基-1-甲基-1H-四唑溶于2.0ml甲酰胺和8.0ml乙腈的混合溶剂中,向其中依次加入1.43g7β-(D-5-苯甲酰氨基-5-羧基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸及1.1ml亚磷酸三甲酯。在20-25℃搅拌1小时。将3ml 2NHCl,和50ml水加入该溶液中,搅拌30分钟,减压浓缩。向浓溶液中加入40ml四氢呋喃-二氯甲烷(1∶1),V/V)的混合溶剂,溶液分两层。分出水层,用20ml上述混合溶剂提取,合并有机层,用15ml水洗涤,用无水硫酸镁干燥。减压浓缩,加乙醚,滤集粉末状沉淀,减压干燥,得1.62g(产率:93.8%)7β-(D-5-苯甲酰氨基-5-羧基戊酰氨基)-3-(1-甲基-1H-四唑基-5)硫甲基-3-头孢烯-4-羧酸。
红外光谱(KBr):3300,2950,1780,1720,1645,1530cm-1
核磁共振(D2O+NaHCO3):δ1.5-2.6(6H,m,-(CH2)3),3.41(2H,ABq,J=17HZ,2-CH2),4.00(3H,S,-CH3),4.15(2H,ABq,J=14HZ,3-CH2),4.44(1H,
br,>CH-),5.20(1H,d,J=5HZ,C6-H),5.56(1H,d,J=5HZ,C7-H,7.3-8.2(5H,m,C6H5-)ppm
实例6
将20ml乙腈和4.66g亚磷酸三丁酯依次加到3.52g7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸双三乙胺盐和1.45g5-巯基-1-甲基-1H-四唑的混合物中,在20-22℃反应1小时。向其中加入70ml水后,减压蒸除大部分乙腈。剩余液中加入30ml二氯甲烷,用1N NaOH调其pH至8.5使沉淀溶解。再用2NHCl调节pH至5.6,溶液分两层。水层中加入60ml四氢呋喃和二氯甲烷混合溶剂(1∶1,V/V),再用2NHCl调节pH至2.0,溶液又分两层,分出有机层,水层用40ml上述混合溶剂提取,合并有机层,用20ml水洗,用无水硫酸镁干燥,减压浓缩,向浓缩液中加入140ml乙醚,滤集沉淀,用乙醚洗涤,减压干燥,得2.86g(产率95.1%)7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-(1-甲基-1H-四唑基-5)硫甲基-3-头孢烯-4-羧酸,本品为一白色粉末。产品的核磁共振光谱与实例1相符。
实例7
将6.0ml的甲酰胺和6.0ml的乙腈加到0.543g1-(2-二甲胺基乙基)-5-巯基-1H-四唑盐酸盐中,制成一混合溶液,将其加到1.00g7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸中,再加入0.50ml亚磷酸三甲酯。在20-25℃并搅拌下反应2.0小时,然后向其中加入30ml乙腈和50ml乙醚,产生了树脂样的物质。倾出上清液,用20ml丙酮洗涤树脂样物质,然后依次加入10ml乙醇,50ml2.5mlHCl的醚溶液(2mol/l),搅拌混合液,滤集粉末状沉淀,用醚洗涤之,减压干燥,得1.27g(产率92.0%)7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-[1-(2-二甲胺基乙基)-1H-四唑基-5]硫甲基-3-头孢烯-4-羧酸盐酸盐。本品为白色粉末。
红外光谱(KBr):3140,3030,1773,1713,1530cm-1
核磁共振(DMSO-d6+D2O):δ1.3-2.4(6H,m,-(CH2)3-),2.92(6H,S,-CH3×2),3.5-3.9(4H,m,2-CH2和-CH2N<),4.30(2H,br,3-CH2),4.5-4.9(3H,m,-CH2CH2N<和>CH-);5.03(1H,d,J=5HZ,C6-H),5.58(1H,d,J=5HZ,C7-H,7.92(4H,S,C6H5-)ppm
实例8
在含有1.31g7β-(D-5-羧基-5-苯氧羰氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸的四氢呋喃(5.0ml)和二氯甲烷(5.0ml)的混合溶液中加入2ml含有0.33g吡啶的四氢呋喃溶液,然后加入0.70ml的亚磷酸三甲酯。反应物在20-25℃搅拌2小时,滤集粉末状沉淀,用10ml四氢呋喃-二氯甲烷混合溶剂(1∶1),V/V)及10ml二氯甲烷洗涤。将产物溶于6.0ml乙腈和水的混合溶剂中(4∶1,V/V),溶液进行硅胶层析,以乙腈-水(4∶1)作洗脱剂。洗脱液进行薄层层析(展开剂∶乙腈∶水∶99%的甲酸=15∶5∶0.25,硅胶板60F-254,E.Merck出品,并用紫外检测),在Rf值0.27处收集所需组分,减压浓缩,冷冻干燥,得1.21g(产率:82.3%)7β-(D-5-羧基-5-苯氧羰氨基戊酰氨基)-3-(1-吡啶鎓)甲基-3-头孢烯-4-羧酸盐。本品为-白色粉末。
红外光谱(KBr):3370,3040,1775,1725,1660,1610cm-1
核磁共振(D2O+NaHCO3):δ1.78(4H,br,-CH2-CH2-),2.39(2H,br,CH2CO),3.30(2H,ABq,J=18HZ,2-CH2),4.02(1H,br,>CH-),5.15(1H,d,J=5HZ,C6-H),5.40(2H,ABq,J=14HZ,3-CH2),5.65(1H,d,J=5HZ,C7-H),7.1-7.6(5H,m,C6H5-),7.8-9.0(5H,m,吡啶)ppm
实例9
将80ml四氢呋喃-二氯甲烷(1∶2,V/V)混合溶剂及1.74g5-巯基-1-甲基-1H-四唑加到4.93g7β-(D-5-羧基-5-苯氧羰氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸中。混合溶液搅拌5分钟,加入3.7ml亚磷酸三甲酯,在20-25℃搅拌3小时。反应液加21ml水,用4NHCl调节pH至2.0,溶液分两层,水层用10ml四氢呋喃和20ml二氯甲烷的混合溶剂提取两次,合并有机层,用盐水洗涤,无水硫酸镁干燥。减压浓缩,浓缩液加乙醚,将固体物质捣碎,滤集粉末状沉淀,
醚洗,减压干燥,得5.23g(产率:88%)7β-(D-5-羧基-5-苯氧羰氨基戊酰氨基)-3-(1-甲基-1H-四唑基-5)硫甲基-3-头孢烯-4-羧酸。
红外光谱(KBr):3270,3020,2920,1780,1725,1530cm-1
核磁共振(DMSO-d6):δ1.4-2.4(6H,m,-(CH2)3),3.69(2H,br,2-CH2),3.94(3H,S,CH3),4.30(2H,br,3-CH2),5.05(1H,d,J=5HZ,C6-H),5.65(1H,q,J=5×8HZ,C7-H),6.9-7.6(5H,m,C6H5-),8.03(1H,d,J=8HZ,OCONH),8.83(1H,d,J=8HZ,CONH)ppm
实例10
将80ml四氢呋喃-二氯甲烷(1∶2,V/V)的混合溶剂,1.74g5-巯基-1-甲基-1H-四唑和4.15g亚磷酸三乙酯加到4.77g7β-[D-5-(对-叔丁基苯甲酰氨基)-5-羧基戊酰氨基]-3-羟甲基-3-头孢烯-4-羧酸中。混合溶液在20-25℃搅拌3小时,用同实例9同样的方法后处理,得5.71g(产率:90%)7β-[D-5-(对-叔丁基苯甲酰氨基-5-羧基戊酰氨基]-3-(1-甲基-1H-四唑基-5)硫甲基-3-头孢烯-4-羧酸。
红外光谱(KBr):3300,2960,1780,1725,1640,1530cm-1
核磁共振(D2O+NaHCO3):δ1.23(9H,S,CH3X3),1.98(4H,br,-CH2CH2-),2.43(2H,br,CH2CO),3.43(2H,ABq,J=17HZ,2-CH2),4.00(3H,S,N-CH3),4.16(2H,ABq,J=14HZ,3-CH2),5.01(1H,d,J=5HZ,C6-H),5.60(1H,d,J=5HZ,C7-H),7.65(4H,d,J=8HZ,-C6H4-)ppm
实例11
将633mg的2-羧基甲硫基-5-巯基-1,3,4-噻二唑在约40℃溶入2ml的甲酰胺和4ml乙腈混合溶剂中。然后将溶液冷却至30℃,依次加入0.31ml亚磷酸三甲酯,689mg7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-羟甲基-3-头-孢烯-4-羧酸三丁基胺盐,0.20ml HCl的醚溶液(5mol/l)。混合溶液在20-25℃搅拌1小时,加20ml水,减压蒸除乙腈。残余物中加10ml四氢呋喃,用4N HCl调节pH至2.6,然后再加15ml二氯甲烷,反应液分两层。分出水层,加入10ml四氢呋喃和15ml二氯甲烷,分出有机层。合并有机层,用盐水洗涤,用无水硫酸镁干燥。蒸除溶剂,残余物进行硅胶层析,得580mg(产率:81%)7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-(2-羧基甲硫基-1,3,4-噻二唑基-5)硫甲基-3-头孢烯-4-羧酸。
红外光谱(KBr):3370,2950,1770,1710,1530,1390cm-1
核磁共振(DMSO-d6+D2O):δ1.3-2.4(6H,m,-(CH2)3-),3.59(2H,br,2-CH2),4.10(2H,br,SCH2CO),4.23(2H,br,3-CH2),4.72(1H,t,J=7HZ,>CH-),5.00(1H,d,J=5HZ,C6-H),5.57(1H,d,J=5HZ,C7-H),7.90(4H,S,C6H4<)ppm
实例12
将689mg7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸的三丁基胺盐加到含有240mg1-羧甲基-5-巯基-1H-四唑的2ml甲酰胺和4ml乙腈的混合溶液中。然后依次向其中加入1.0ml HCl的四氢呋喃溶液(1mol/l),0.30ml亚磷酸三甲酯,搅拌混合液。向反应液中加20ml水,减压蒸除乙腈。浓缩液加10ml四氢呋喃,用4N HCl调节pH至2.6,加入15ml二氯甲烷后进行分离。合并有机层,盐水洗涤,用无水硫酸镁干燥。减压浓缩,浓缩液倾入醚中,滤集粉末状沉淀,减压干燥,得507mg(产率:82%)3-(1-羧甲基-1H-四唑基-5)硫甲基-7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-头孢烯-4-羧酸。
红外光谱(KBr):3300,2940,1770,1710,1530,1390cm-1
核磁共振(DMSO-d6+D2O):δ1.3-2.4(6H,m,-(CH2)3-),3.59(2H,br,2-CH2),4.10(2H,br,SCH2CO),4.23(2H,br,3-CH2),4.72(1H,t,J=7HZ,>CH-),5.00(1H,d,J=5HZ,C6-H),5.57(1H,d,J=5HZ,C7-H),7.90(4H,S,C6H4<)ppm
实例13
在含有265mg4,6-二甲基-2-巯基-嘧啶盐酸盐的3.5ml甲酰胺和4ml乙腈的混合溶液中,依
次加入0.31ml亚磷酸三甲酯,689mg7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸三丁基胺盐。混合物在20-25℃搅拌1.5小时,用同实例12同样的方法后处理,得573mg(产率:91%),7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-(4,6-二甲基嘧啶基-2)硫甲基-3-头孢烯-4-羧酸。
红外光谱(KBr):3260,2950,1775,1715,1580,1530cm-1
核磁共振(DMSO-d6):δ1.3-2.3(6H,m,(-CH2)3-),2.35(6H,S,CH3×2),3.55(2H,ABq,J=18HZ,2-CH2),4.15(2H,ABq,J=14HZ,3-CH2),4.78(1H,br,>CH-),4.99(1H,d,J=5HZ,C6-H),5.56(1H,q,J=5×8HZ,C7-H),6.93(1H,S,嘧啶),7.87(4H,S,C6H4<),8.22(1H,d,J=8HZ,CONH)ppm
实例14
在1.01g7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸中依次加入10ml四氢呋喃,15ml二氯甲烷,0.70g2-乙氧羰基甲硫基-5-巯基-1,3,4-噻二唑,0.70g亚磷酸三乙酯。混合物在20-25℃搅拌2小时。向反应液中加入10ml水,用4N HCl调节pH至2.5,溶液分两层。水层用10ml四氢呋喃和15ml二氯甲烷的混合溶剂提取,合并有机层,用盐水洗涤,用无水硫酸镁干燥。减压浓缩,将浓缩液溶于少量丙酮中,然后将其倾入醚中,滤集粉末状沉淀,减压干燥,得1.12g(产率:87%)7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-(2-乙氧羰基甲硫基-1,3,4-噻二唑基-5)硫甲基-3-头孢烯-4-羧酸。
红外光谱(KBr):3300,2950,1775,1715,1530,1490cm-1
核磁共振(DMSO-d6):δ1.20(3H,t,CH3),1.4-2.4(6H,m-(CH2)3-),3.62(2H,br,2-CH2),3.9-4.5(6H,m,COCH2,SCH2CO,3-CH2),4.75(1H,t,J=7HZ,>CH-),5.06(1H,d,J=5HZ,C6-H),5.66(1H,br,C7-H),7.90(4H,S,C6H4<),8.33(1H,br,CONH)ppm
实例15
在2.01g7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸中依次加入4ml甲酰胺,4ml乙腈,0.95吡啶和1.51ml亚磷酸三甲酯。混合物在20-25℃搅拌2小时。冷却反应液,加入40ml乙腈和20ml醚,产生树脂样沉淀,倾出上清液,沉淀用乙腈洗涤两次,每次10ml。然后向其中加入50ml新鲜的乙腈,将沉淀捣碎,得到均匀的粉末,滤集粉末状沉淀,用乙腈洗涤,减压干燥,得1.90g(产率:84%)7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-(1-吡啶鎓)甲基-3-头孢烯-4-羧酸盐。
红外光谱(KBr):3420,3060,2950,1770,1710,1390cm-1
核磁共振(D2O+NaHCO3):δ1.30-2.60(6H,m,-(CH2)3),3.19(2H,ABq,J=18HZ,2-CH2),5.90(1H,d,J=5HZ,C6-H),5.47(2H,ABq,J=13HZ,3-CH2),5.61(1H,d,J=5HZ,C7-H),7.80(4H,S,C6H4<),8.0-9.1(5H,m,吡啶)ppm
实例16
在1.51g7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸中,依次加入6ml甲酰胺,1.10g异烟酰胺,6ml乙腈。搅拌5分钟后,再加入0.75ml亚磷酸三甲酯,混合液在20-25℃搅拌2小时。然后向其中加入40ml乙腈和20ml醚,冷却反应液,分出反应产生的树脂样物质,用乙腈洗涤,然后将其溶入20ml水和乙腈(1∶2,V/V)的混合溶剂中,用1N NaOH调节pH至6.0,减压浓缩,浓缩液用大网状树脂-2(100ml)进行柱层析,以水以及水和乙腈的混合溶剂作洗脱剂。收集含有终产物的组分,调节pH至6.0,减压浓缩,冷冻干燥,得7β-(D-5-羧基-5-邻苯二甲酰亚氨基戊酰氨基)-3-(4-氨基甲酰基-1-吡啶鎓)甲基-3-头孢烯-4-羧酸钠。
红外光谱(KBr):3380,1765,1705,1610,1460,1395cm-1
核磁共振(D2O):δ1.4-2.6(6H,m,-(CH2)3-),3.26(2H,ABq,J=18HZ,2-CH2),4.58(1H,t,J=7HZ,>CH-),5.11(1H,d,J=5HZ,C6-H),5.53(2H,ABq,
J=13HZ,3-CH2),5.61(1H,d,J=5HZ,C7-H),7.78(4H,s,C6H4<),8.42 & 9.16(4H,分别为d,J=7HZ,吡啶)ppm
实例17
将1.43g7β-(D-5-苯甲酰氨基-5-羧基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸溶于6ml甲酰胺中,然后依次加入6ml乙腈,0.95g吡啶和1.1ml亚磷酸三甲酯,反应在20-25℃进行两小时,然后加入60ml乙腈,将其冷却。倾出上清液后,余下的胶样物质用乙腈洗涤,然后加20ml水和乙腈(1∶1,V/V)的混合溶剂,用1N NaOH调节pH至6.0,减压蒸除乙腈。残余物以水作洗脱剂,用大网状树脂-2(100ml)进行柱层析。含有终产物的各组分合并,冷冻干燥,得7β-(D-5-苯甲酰氨基-5-羧基-戊酰氨基)-3-(1-吡啶鎓)甲基-3-头孢烯4-羧酸钠。
红外光谱(KBr):3400,3050,1770,1610,1535,1485cm-1
核磁共振(D2O):δ1.50-2.60(6H,m,-(CH2)3-),3.19(2H,ABq,J=18HZ,2-CH2),4.37(1H,br,>CH-),5.11(1H,d,J=5HZ,C6-H),5.23(2H,ABq,J=14HZ,3-CH2)5.64(1H,d,J=5HZ,C7-H),7.30-9.10(10H,m,C6H5-和吡啶)ppm
实例18
将2ml甲酰胺,3ml乙腈和0.85g的异烟酰胺加到1.73g7β-(D-5-羧基-5-苯氧羰氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸中,搅拌混合物,在5分钟之内加入1.1ml的亚磷酸三甲酯,于20-25℃搅拌2小时。向生成物中加入1ml水,静置10分钟,然后再加10ml乙腈,该反应液进行硅胶层析(用60g硅胶),以水和乙腈(1∶4,V/V)的混合溶剂作洗脱剂,将含有终产物的各组分合并,用1N NaOH调节pH至6.5,减压浓缩,冷冻干燥,得7β-(D-5-羧基-5-苯氧羰氨基戊酰氨基)-3-(4-氨基甲基-1-吡啶鎓)甲基-3-头孢烯4-羧酸钠盐。
红外光谱(KBr):3400,1770,1725,1690,1610cm-1
核磁共振(D2O):δ1.5-2.6(6H,m,-(CH2)3-),3.35(2H,ABq,J=17HZ,2-CH2),4.02(1H,br,>CH-),5.17(1H,d,J=5HZ,C6-H),5.47(2H,ABq,3-CH2),5.56(1H,d,J=5HZ,C7-H),7.0-7.6(5H,m,C6H5-),8.32和9.11(4H,分别为d,J=8HZ,吡啶)ppm
实例19
将1.93g亚磷酸三乙酯加到含有1.22g1-(2-二甲基乙基)-5-巯基-1H-四唑盐酸盐的5ml甲酰胺和4ml乙腈的混合溶液中,然后将含有2.47g7β-(D-5-羧基-5-苯氧羰氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸的5ml甲酰胺和5ml乙腈的混合液加到上述混合溶液中。整个混合液搅拌10分钟,加2ml水,静置10分钟。减压蒸除乙腈,残余物倒入200ml冷水中,滤集沉淀,水洗,然后溶于乙腈和水(4∶1,V/V)的混合溶剂中。上述溶液用50g硅胶进行柱层析,以乙腈和水(4∶1,V/V)的混合溶剂作洗脱剂,合并含有终产物的组分,减压浓缩,冷冻干燥,得7β-(D-5-羧基-5-苯氧羰氨基戊酰氨基)-3-[1-(2-二甲氨基乙基)-1H-四唑基-5]硫甲基-3-头孢烯-羧酸。
红外光谱(KBr):3300,1760,1725,1600,1530cm-1
核磁共振(D2O+NaHCO3):δ1.81(4H,br,-CH2CH2-),2.40(2H,br,CH2CO),2.63(6H,S,N(CH3)2),3.31(2H,t,J=6HZ,CH2N),3.56(2H,ABq,J=18HZ,2-CH2),4.20(2H,br,3-CH2),5.07(1H,d,J=5HZ,C6H),5.57(1H,d,J=5HZ,C7-H),7.0-7.6(5H,m,C6H5-),ppm
实例20
将溶于2ml甲酰胺和8ml乙腈的0.79g5-巯基-2-甲基-1,3,4-噻二唑加到1.52g7β-(D-5-苄氧-羰氨基-5-羧基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸中,再向其中加入1.25g亚磷酸三甲酯,于20-25℃下搅拌3小时。加15m水,搅拌10分钟,减压蒸除乙腈,残余液中加10ml四氢呋喃,用22NHCl调节pH至2.6,加15ml二氯甲烷使混合液分为两层。水层用6ml四氢呋喃和9ml二氯甲烷的混合溶剂提取两次以上,提取液同有机层合并,用盐水洗涤,用无水硫酸镁干燥。减压浓缩,浓缩液溶入少量丙酮中,后倒入乙醚中。滤集
沉淀物质,乙醚洗,减压干燥,得1.55g(产率:83%)的7β-(D-5-苄氧羰氨基-5-羧基戊酰氨基)-3-(2-二甲基-1,3,4-噻二唑基-5)硫甲基-3-头孢烯-4-羧酸。
红外光谱(KBr):3280,2940,1775,1715,1530cm-1
核磁共振(DMSO-d6):δ1.65(4H,br,-CH2CH2-),2.17(2H,br,CH2CO),2.68(2H,S,CH3),3.63(2H,br,2-CH2),4.36(2H,ABq,J=14HZ,3-CH2),5.00(3H,br,CH2OCO和C6-H和>CH-),5.62(1H,br,C7-H),7.33(6H,m,C6H5-和CONH),8.80(1H,br,CONH)ppm
实例21
将含有0.70g5-巯基-1-甲基-1H-四唑的2ml甲酰胺和8ml乙腈的混合液以及1.25g亚磷酸三乙酯,依次加到1.34g7β-(D-5-羧基-5-乙氧羰氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸中,在20-25℃搅拌3小时。反应液用和实例20同样的方法后处理,得1.39g(产率:85%)7β-(D-5-羧基-5-乙氧羰氨基戊酰氨基)-3-(1-甲基-1H-四唑基-5)硫甲基-3-头孢烯-4-羧酸。
红外光谱(KBr):3350,2960,1777,1710,1530cm-1
核磁共振(DMSO-d6):δ1.16(3H,t,J=7HZ,CH2CH3),1.61(4H,br,-(CH2)2-),2.18(2H,br,CH2CO),3.67(2H,br,2-CH2),3.93(3H,S,N-CH3),3.96(2H,q,J=7HZ,CH2CH3),4.29(2H,br,3-CH2),5.04(1H,d,J=5HZ,C6-H),5.63(1H,q,J=8×5HZ,C7-H),7.26(1H,d,J=8HZ,OCONH),8.76(1H,d,J=8HZ,CONH)ppm
实例22
将418mg的7β-(D-5-二苯基甲氧羰基-5-邻苯二甲酰亚氨基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸二苯基甲酯和116mg5-巯基-1-甲基-1H-四唑溶于4ml乙酸乙酯中。向上述溶液加入166mg亚磷酸三乙酯,于20-25℃搅拌1小时。加1ml正己烷。该混合液进行硅胶层析,以乙酸乙酯和正己烷(4∶1,V/V)的混合溶剂作洗脱剂。合并含有终产物的组分,减压浓缩。浓缩物中加醚,滤集粉末状沉淀,减压干燥,得7β-(D-5-二苯基甲氧羰基-5-邻苯二甲酰亚氨基戊酰氨基)-3-(1-甲基-1H-四唑基-5)硫甲基-3-头孢烯-4-羧酸二苯基甲酯。
红外光谱(KBr):3350,3030,2930,1775,1715cm-1
核磁共振(DMSO-d6):δ1.30-2.40(6H,m,-(CH2)3-),3.68(2H,br,2-CH2),3.88(3H,S,N-CH3),4.24(2H,br,3-CH2),4.90-5.20(2H,m,C6-H和>CH-),5.73(1H,q,J=5×8HZ),6.83和6.90(2H,S,-CSOCH<×2),7.10-7.60(20H,m,C6H5-×4),7.91(4H,S,C6H4<),8.87(1H,d,J=8HZ,-CONH-)ppm
实例23
将1ml甲酰胺和3ml乙腈加到477mg7β-(D-5苯甲酰氨基-5-羧基戊酰氨基)-3-羟甲基-3-头孢烯-4-羧酸和114mg的硫脲中形成溶液,向该溶液加248mg亚磷酸三甲酯,于20-25℃搅拌2小时。生成物中加50ml乙腈,滤集结晶状沉淀,用乙腈洗涤,干燥,得466mg(产率:87%)7β-(D-5-苯甲酰氨基-5-羧基戊酰氨基)-3-氨甲酰亚氨酰基硫甲基-3-头孢烯-4-羧酸。
红外光谱(KBr):3270,3050,1765,1645,1600,1580,1535cm-1
核磁共振(D2O+NaHCO3):δ1.5-2.6(6H,m,-(CH2)3-),3.45(2H,S,2-CH2),3.6-4.6(3H,m,3-CH2和>CH-),5.07(1H,d,J=5HZ,C6-H),5.56(1H,d,J=5HZ,C7-H),7.4-8.2(5H,m,C6H5-)ppm
实例24
加12ml乙酸乙酯到582mg7β-[2-(2-噻吩基)乙酰氨基]-3-羟甲基-3-头孢-4-羧酸和174mg5-巯基-1-甲基-1H-四唑中成溶液,向该溶液中依次加入0.25ml的亚磷酸三甲酯和0.2mlHCl的醚溶液(5mol/L),于20-25℃下搅拌3小时。向反应液中加10ml水,用2N HCl调节pH至2,溶液分两层,分出水层,加10ml乙酸乙酯,又分两层,合并有机层,用5ml盐水洗
涤,用无水硫酸镁干燥,减压浓缩,浓缩液中加醚,滤集粉末状沉淀,洗涤,干燥,得804mg(产率:89%)3-(1-甲基-1H-四唑基-5)硫甲基-7β-[2-(2-噻吩基)乙酰氨基]-3-头孢烯-4-羧酸。
红外光谱(KBr):1776,1734,1672cm-1
核磁共振(DMSO-d6):δ3.67(2H,ABq,J=18HZ,2-CH2),3.73(2H,S,CH2CO),3.92(3H,S,N-CH3),4.29(2H,ABq,J=13HZ,3-CH2),5.05(1H,d,J=5HZ,C6-H),5.66(1H,q,J=5×8HZ,C7-H),6.90和7.29(3H,噻吩基)9.10(1H,d,J=8HZ,CONH)ppm
实例25
450mg7β-(2-苯基乙酰氨基)-3-羟甲基-3-头孢烯-4-羧酸三乙基胺盐,用和实例24同样的方法进行反应和后处理,得385mg(产率:86%)3-(1-甲基-1H-四唑基-5)硫甲基-7β-(2-苯基乙酰氨基)-3-头孢烯-4-羧酸。
红外光谱(KBr):1780,1720,1668cm-1
核磁共振(DMSO-d6+D2O):δ3.56(2H,S,CH2CO),3.69(2H,br,2-CH2),3.95(3H,S,N-CH3),4.27(2H,br,3-CH2),5.03(1H,d,J=4.5HZ,C6-H),5.63(1H,d,J=4.5HZ,C7-H),7.30(5H,S,C6H5-)ppm
实例26
将423mg7β-[2-(2-氨基噻唑基-4)乙酰氨基-3-羟甲基-3-头孢烯-4-羧酸钠盐二水合物悬浮于4ml甲酰胺和4ml乙腈的混合溶剂中。向该悬浮液中依次加入315mg1-(2-二甲氨基乙基)-5-巯基-1H-四唑盐酸盐,0.45ml亚磷酸三甲酯和0.20mlHCl的醚溶液(5mol/l),在20-25℃搅拌1.5小时,加5ml水,于20-25下减压浓缩。浓缩液中加50ml水,用1N NaOH调节pH至5.8,然后用大网状树脂-2进行柱层析,以水和丙酮(4∶1,V/V)的混合溶剂作洗脱剂。合并含有终产物的各组分,减压浓缩,冷冻干燥,得7β-[2-(2-氨基噻唑基-4)乙酰氨基]-3-[1-(2-二甲氨基乙基)-1H-四唑基-5]硫甲基-3-头孢烯-4-羧酸。
红外光谱(KBr):3320,1765,1670,1610cm-1
核磁共振(D2O):δ3.30(6H,S,-N(CH3)2),3.3~4.0(6H,m,CH2CO和2-CH2和-CH3)2N<),4.21(2H,br,3-CH2),4.88(2H,t,J=6HZ,N-CH2),5.10(1H,d,J=5HZ,C6-H),5.63(1H,d,J=5HZ,C7-H),6.50(1H,S,噻唑)ppm
实例27
将103mg7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-羟甲基-3-头孢烯-4-羧酸悬浮于2ml乙腈中。依次向该悬浮液中加入0.10ml吡啶,0.21ml亚磷酸三乙酯和0.2ml醋酸,于20-25℃搅拌8小时,减压浓缩。浓缩液中加10ml四氢呋喃,滤集粉末状沉淀,减压浓缩(干燥),得7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-(1-吡啶鎓基)甲基-3-头孢烯-4-羧酸盐。
红外光谱(KBr):3350,1771,1660,1620cm-1
核磁共振(D2O):δ3.18和3.65(2H,ABq,J=18HZ,2-CH2)3.94(3H,S,OCH3),5.23(1H,d,J==5HZ,C6-H),5.30和5.56(2H,ABq,J=15HZ,3-CH2),5.80(1H,d,J=5HZ,C7-H),6.19(1H,S,噻唑)7.9~8.2和8.4~9.0(2H和3H,m,吡啶)ppm
实例28
将103mg7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲基亚氨基乙酰氨基]-3-羟甲基-3-头孢烯-4-羧酸悬浮于2ml乙腈中。依次向该悬浮液中加入0.15ml的2,3-环戊烯并吡啶。,0.21ml亚磷酸三乙酯和0.2ml的乙酸,于20-25℃搅拌5.5小时。再加入0.1ml的醋酸,继续搅拌1小时。减压浓缩。浓缩液中加10ml四氢呋喃,滤集粉末状沉淀,减压干燥,得7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-(2,3-环戊烯基-1-吡啶鎓基)甲基-3-头孢烯-4-羧酸盐。
红外光谱(KBr):3350,1765,1665,1615cm-1
核磁共振(D2O+NaHCO3):δ2.0-2.5(2H,m,-CH2CH2CH2-),3.0-3.5(4H,m,
-CH2CH2CH2-),3.16和3.46(2H,ABq,J=18HZ,2-CH2),3.94(3H,S,OCH3),5.20(1H,d,J=5HZ,C6-H),5.23和5.47(2H,ABq,J=17HZ,3-CH2),5.79(1H,d,J=5HZ,C7-H),6.84(1H,S,噻唑)7.5-7.8和8.05-8.55(1H,和2H,m吡啶)ppm
实例29
将207mg7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-羟甲基-3-头孢-4-羧酸悬浮于4ml乙腈中。,依次向该悬浮液中加343mg烟酸甲酯,0.43ml亚磷酸三乙酯和0.4ml乙酸,在20-25℃搅拌7小时,减压浓缩。浓缩液中加10ml四氢呋喃,滤集粉末状沉淀,减压干燥,得218mg(产率:82%)7β-[2-2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-(3-甲氧羰基-1-吡啶鎓基)甲基-3-头孢烯-4-羧酸盐。
红外光谱(KBr):3375,1770,1735,1665,1620cm-1
核磁共振(D2O+NaHCO3):δ3.18和3.17(2H,ABq,J=18HZ,2-CH2)3.94(3H,S,NOCH3),4.01(3H,S,COOCH3),5.26(1H,d,J=5HZ,C6-H),5.34和5.69(2H,ABq,J=15HZ,3-CH2),5.78(1H,d,J=5HZ,C7-H),6.81(1H,S,噻唑)8.0-8.3和8.8-9.25(1H,和2H,m,吡啶)9.55(1H,br,吡啶)ppm
实例30
将207mg7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-羟甲基-3-头孢-4-羧酸悬浮于4ml乙腈中。依次向悬浮液中加入0.25mlα-甲基吡啶,0.43ml亚磷酸三乙酯和0.4ml乙酸,于20-25℃下搅拌7小时,减压浓缩,将10ml四氢呋喃加到浓缩液中,滤集粉末状沉淀,减压干燥,得7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-(2-甲基-1-吡啶鎓基)甲基-3-头孢烯-4-羧酸盐。
红外光谱(KBr):3350,1770,1660,1620cm-1
核磁共振(D2O+NaHCO3):δ2.81(3H,S,CH3),3.17和3.50(2H,ABq,J=18HZ,2-CH2),3.95(3H,S,OCH3),5.22(1H,d,J=5HZ,C6-H),5.28和5.53(2H,ABq,J=17HZ,3-CH2),5.81(1H,d,J=5HZ,C7-H),6.90(1H,S,噻唑),7.6-7.95和8.15-8.45及8.55-8.75(2H和1H及1H,m,吡啶)ppm
实例31
将207mg7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-羟甲基-3-头孢烯-4-羧酸和183mg的异烟酰胺溶于1ml甲酰胺中,依次向该溶液中加入2ml乙腈,0.43ml亚磷酸三乙酯和0.2ml醋酸,于20-25℃搅拌3小时,减压浓缩。将浓缩液慢慢滴加到50ml四氢呋喃中,滤集粉末状沉淀,减压干燥,得7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-(4-氨基甲酰基-1-吡啶鎓基)甲基-3-头孢烯-4-羧酸盐。
红外光谱(KBr):3250,3150,1765,1680,1615cm-1
核磁共振(D2O+NsHCO3):δ3.21和3.70(2H,ABq,J=18HZ,2-CH2),3.95(3H,S,OCH3),5.26(1H,d,J=5HZ,C6-H),5.37和5.67(2H,ABq,J=15HZ,3-CH2),5.80(1H,d,J=5HZ,C7-H),6.87(1H,S,噻唑),8.31和9.08(分别为2H,d,J=7HZ,吡啶)ppm
实例32
将413mg7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-羟甲基-3-头孢烯-4-羧酸和0.36g的咪唑并[1,2-a]吡啶溶于1ml甲酰胺中,依次向该溶液中加入2ml乙腈,0.86ml亚磷酸三乙酯和0.81ml的醋酸,在20-25℃搅拌14小时,减压浓缩。将浓缩液慢慢滴加到70ml四氢呋喃中,滤集粉末状沉淀。将该粉末溶于20ml水中,用大网状树脂-2进行柱层析,以水和乙腈(9∶1,V/V)的混合溶剂作洗脱剂。合并含有终产物的各组分,减压浓缩,冷冻干燥,得7β-[2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-(咪唑并[1,2-a]吡啶鎓基-1)甲基-3-头孢烯-4-羧酸盐。
红外光谱(KBr):3375,1765,1610cm-1
核磁共振(DMSO-d6):δ2.97和3.44(2H,ABq,J=17HZ,2-CH2),3.77(3H,S,
OCH3),4.97(1H,d,J=5HZ,C6-H),5.22和5.35(2H,ABq,J=14HZ,3-CH2),5.58(1H,dd,J=5×8HZ,C7-H),6.65(1H,S,噻唑),7.13(2H,br,NH2),7.35-7.6和7.8-8.1及8.25-8.7又及8.8-8.95(1H和1H及3H又及1H,m,咪唑并吡啶),9.41(1H,d,J=8HZ,CONH)ppm
实例33
将413mg7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-羟甲基-3-头孢烯-4-羧酸和354mg的咪唑并[1,5-a]吡啶溶于1ml甲酰胺中,加1ml乙腈和0.86ml亚磷酸三乙酯,于20-25℃下搅拌10小时。生成物用和实例32同样的方法后处理,得7β-[2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-(咪唑并[1,5-a]吡啶鎓基-2)甲基-3-头孢烯-4-羧酸盐。
红外光谱(KBr):3375,1765,1655,1610cm-1
核磁共振(DMSO-d6):δ3.13和3.45(2H,ABq,J=18HZ,2-CH2),3.77(3H,S,OCH3),5.00(1H,d,J=5HZ,C6-H),5.04和5.51(2H,ABq,J=15HZ,3-CH2),5.59(1H,dd,J=5×8HZ,C7-H),6.66(1H,S,噻唑),7.13(2H,br,NH2),6.9-7.4和7.7-7.9及8.4-8.7(2H和1H及1H,m)和8.47和10.03(分别为1H,br,咪唑并吡啶),9.37(1H,d,J=8HZ,CONH)ppm
实例34
将413mg7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-羟甲基-3-头孢烯-4-羧酸和357mg的咪唑并[1,2-b]哒嗪溶于1ml甲酰胺中,再加1ml甲酰胺和0.86ml亚磷酸三乙酯,于20-25℃下搅拌5小时。以同实例32同样的方法进行后处理,得7β-[2-(2-氨基噻唑基-4)-2-(顺)-甲氧亚氨基乙酰氨基]-3-(咪唑并[1,2-b]哒嗪基-1)甲基-3-头孢烯-4-羧酸盐。
红外光谱(KBr):3375,1765,1665,1610cm-1
核磁共振(DMSO-d6):δ3.30和3.48(2H,ABq,J=18HZ,2-CH2),3.77(3H,S,OCH3),4.98(1H,d,J=5HZ,C6-H),5.25和5.51(2H,ABq,J=14HZ,3-CH2),5.59(1H,dd,J=5×8HZ,C7-H),6.65(1H,S,噻唑),7.13(2H,br,NH2),7.90(1H,dd,J=4×9HZ)和8.37(2H,br)和8.99(1H,d,J=4HZ)和9.27(1H,d,J=9HZ,咪唑并哒嗪)8.42(1H,d,J=8HZ,CONH)ppm。
Claims (6)
3、按照权利要求1的方法,其中虚线表示头孢烯环3位上的双键。
4、按照权利要求1的方法,其中亲核化合物是含氮亲核化合物。
5、按照权利要求1的方法,其中亲核化合物是含硫亲核化合物。
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EP (1) | EP0234549B1 (zh) |
JP (1) | JPH082908B2 (zh) |
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CN (1) | CN1024011C (zh) |
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CA (1) | CA1293718C (zh) |
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US5587474A (en) * | 1992-06-18 | 1996-12-24 | Tanabe Seiyaku Co., Ltd. | Method for removing the protecting group for carboxyl group |
EP1635858A4 (en) * | 2003-05-29 | 2009-08-26 | Scripps Research Inst | TARGETED RELEASE ON CELLS EXPRESSING LEGUMINUM |
CN101374856A (zh) * | 2005-11-29 | 2009-02-25 | 斯克里普斯研究学院 | 抑制肿瘤细胞浸润、转移和血管生成 |
US8198434B2 (en) * | 2008-05-07 | 2012-06-12 | Idexx Laboratories, Inc. | Process for preparing cefsulodin sodium |
CN110950816B (zh) * | 2019-12-13 | 2021-07-06 | 山东金城医药化工有限公司 | 1-(2-二甲基氨基乙基)-5-巯基四唑的合成方法 |
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HUT44560A (en) | 1988-03-28 |
DE3783048D1 (de) | 1993-01-28 |
HU198499B (en) | 1989-10-30 |
JPH082908B2 (ja) | 1996-01-17 |
EP0234549A3 (en) | 1989-05-31 |
US4980464A (en) | 1990-12-25 |
ATE83486T1 (de) | 1993-01-15 |
DE3783048T2 (de) | 1993-04-15 |
KR870007938A (ko) | 1987-09-23 |
CA1293718C (en) | 1991-12-31 |
JPS62277389A (ja) | 1987-12-02 |
EP0234549A2 (en) | 1987-09-02 |
CN87101581A (zh) | 1987-09-30 |
ES2052501T3 (es) | 1994-07-16 |
KR930007808B1 (ko) | 1993-08-20 |
EP0234549B1 (en) | 1992-12-16 |
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